Systematic evidence review and meta-analysis of outcomes associated with cancer genetic counseling.

PURPOSE: Genetic counseling (GC) is standard of care in genetic cancer risk assessment (GCRA). A rigorous assessment of the data reported from published studies is crucial to ensure the evidence-based implementation of GC. METHODS: We conducted a systematic review and meta-analysis of 17 patient-reported and health-services-related outcomes associated with pre- and post-test GC in GCRA in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. RESULTS: Twenty-five of 5393 screened articles met inclusion criteria. No articles reporting post-test GC outcomes met inclusion criteria. For patient-reported outcomes, pre-test GC significantly decreased worry, increased knowledge, and decreased perceived risk but did not significantly affect patient anxiety, depression, decisional conflict, satisfaction, or intent to pursue genetic testing. For health-services outcomes, pre-test GC increased correct genetic test ordering, reduced inappropriate services, increased spousal support for genetic testing, and expedited care delivery but did not consistently improve cancer prevention behaviors nor lead to accurate risk assessment. The GRADE certainty in the evidence was very low or low. No included studies elucidated GC effect on mortality, cascade testing, cost-effectiveness, care coordination, shared decision making, or patient time burden. CONCLUSION: The true impact of GC on relevant outcomes is not known low quality or absent evidence. Although a meta-analysis found that pre-test GC had beneficial effects on knowledge, worry, and risk perception, the certainty of this evidence was low according to GRADE methodology. Further studies are needed to support the evidence-based application of GC in GCRA.

Impact of integrated translational research on clinical exome sequencing.

PURPOSE: Exome sequencing often identifies pathogenic genetic variants in patients with undiagnosed diseases. Nevertheless, frequent findings of variants of uncertain significance necessitate additional efforts to establish causality before reaching a conclusive diagnosis. To provide comprehensive genomic testing to patients with undiagnosed disease, we established an Individualized Medicine Clinic, which offered clinical exome testing and included a Translational Omics Program (TOP) that provided variant curation, research activities, or research exome sequencing. METHODS: From 2012 to 2018, 1101 unselected patients with undiagnosed diseases received exome testing. Outcomes were reviewed to assess impact of the TOP and patient characteristics on diagnostic rates through descriptive and multivariate analyses. RESULTS: The overall diagnostic yield was 24.9% (274 of 1101 patients), with 174 (15.8% of 1101) diagnosed on the basis of clinical exome sequencing alone. Four hundred twenty-three patients with nondiagnostic or without access to clinical exome sequencing were evaluated by the TOP, with 100 (9% of 1101) patients receiving a diagnosis, accounting for 36.5% of the diagnostic yield. The identification of a genetic diagnosis was influenced by the age at time of testing and the disease phenotype of the patient. CONCLUSION: Integration of translational research activities into clinical practice of a tertiary medical center can significantly increase the diagnostic yield of patients with undiagnosed disease.

A second cohort of CHD3 patients expands the molecular mechanisms known to cause Snijders Blok-Campeau syndrome.

There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 (CHD3), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.

De novo DDX3X missense variants in males appear viable and contribute to syndromic intellectual disability.

DDX3X (Xp11.4) encodes a DEAD-box RNA helicase that escapes X chromosome inactivation. Pathogenic variants in DDX3X have been shown to cause X-linked intellectual disability (ID) (MRX102, MIM: 300958). The phenotypes associated with DDX3X variants are heterogeneous and include brain and behavioral abnormalities, microcephaly, hypotonia, and movement disorders and/or spasticity. The majority of DDX3X variants described are de novo mutations in females with ID. In contrast, most male DDX3X variants are inherited from an unaffected mother, with one documented exception being a recently identified de novo splice site variant. It has been suggested, therefore, that DDX3X exerts its effects through haploinsufficiency in females, and that affected males carry hypomorphic alleles that retain partial function. Given the lack of male de novo DDX3X variants, loss-of-function variants in this gene are suspected to be male lethal. Through whole-exome sequencing, we identified three unrelated males with hemizygous missense DDX3X variants and ID. All three variants were confirmed by Sanger sequencing, with two established as de novo. In silico analyses were supportive of pathogenicity. We report the male phenotypes and compare them to phenotypes observed in previously reported male and female patients. In conclusion, we propose that de novo DDX3X variants are not necessarily male lethal and should be considered as a cause of syndromic ID in both males and females.